This grant application responds to PA-15-169: Secondary Analyses in Obesity, Diabetes and Digestive and Kidney Diseases (R21) with an exploratory/developmental application designed to determine whether a copy number variant in salivary amylase (AMY1), recently shown for the first time to be associated with body mass index (BMI), 1) associates with BMI, dietary intake, fasting insulin and glucose in European-, African- and Hispanic-Americans, and 2) predicts weight loss, weight loss maintenance, insulin resistance and/or diabetes outcomes in two large behavioral weight loss trials. Specifically, we propose to add de novo genotyping of three variants in the AMY1 region (AMY1 CNV, AMY2 CNV and a new AMY1 microsatellite), and conduct secondary data analyses leveraging existing data from two of the largest behavioral weight loss trials conducted to date. Look AHEAD (Action for Health and Diabetes) Study is a multi-center randomized controlled trial with the primary goal of determining whether weight loss achieved through an intensive lifestyle intervention (ILI) can improve health outcomes among persons with type 2 diabetes. The Diabetes Prevention Program (DPP), a randomized clinical trial testing whether lifestyle intervention or metformin prevents or delays type 2 diabetes in high-risk individuals, provides an excellent replication cohort due to similarity in lifestyle intervention and dietary measurement. DPP further tracked insulin resistance and incidence of diabetes, providing a unique opportunity to test whether AMY1 predicts diabetes incidence over time and whether behavioral weight loss treatment may mitigate this association. Given the successful weight loss, excellent retention, large samples sizes with genetic consent (>7,000 combined) and extensive data collection in both of these studies, they provide outstanding opportunities to cost-effectively explore the role of the AMY1 region in BMI and diet as well as treatment outcomes related to weight loss, weight loss maintenance, and incidence of type 2 diabetes. Overall, this proposal will expand the breadth of knowledge regarding the phenotypes predicted by AMY1 and test for the first time potential treatment implications, beginning to lay the groundwork for optimizing obesity treatment and diabetes prevention based on AMY1 copy number.